Recent advances in medicine have produced several alternative modes of drug delivery. Drugs which were previously only available in injectable forms, are now available in less invasive forms such as oral tablets or capsules, sustained release devices, and transdermal patches. Many of these advances, however, have occurred with protein based or small molecule drugs. Delivery of polysaccharides for therapeutic or prophylactic purposes is still associated with some problems.
Oral delivery of drugs is often preferred. The rapid metabolism of polysaccharides in the gastrointestinal tract, however, has prohibited their oral administration. Pulmonary delivery of drugs has also been proposed to be a preferred route of drug administration because of the large surface area of blood vessels in alveoli. The thin barrier between the rich capillary bed and the air coupled with the very high blood flow rate makes alveoli of lungs one of the most desirable drug delivery sites. Pulmonary delivery of protein based drugs has been quite successful. Investigators, however, have been trying for over 30 years to administer polysaccharides such as heparin by pulmonary delivery, with much less success. For instance, delivering heparin by conventional liquid aerosol spray or instillation only received limited success due to its poor penetration to the deep lung and resultant poor pharmacokinetics performance. An exceedingly high dose of heparin is required to generate meaningful pharmacological effects when inhaled as liquid heparin.
Natural polysaccharides such as heparin are polydisperse mixtures containing a large number of chains having different molecular weights (MWs) and as such the pharmacokinetics of these compounds are complicated. The anticoagulant response of heparin, for instance, increases disproportionately in intensity and duration as the dose increases. As a result, anticoagulant effect of heparin often has to be closely monitored to minimize the occurrence of potentially dangerous hemorrhage, which is the most common and major side effect of heparin. Since heparin is not a single chemical entity and its disposition is determined by a number of pathophysiologic factors, its pharmacokinetic parameters vary substantially among different individuals and thus require dose adjustment for each specific individual. The frequency of side effects is associated with the routes of administration. The risk is higher in intermittent (14.2%) and continuous (6.8%) infusion than the subcutaneous route (4.1%).